This approach was initially based upon the discovery by Hans Lilja at the University of Lund, Sweden, that Prostate-Specific Antigen (PSA), besides being a serum marker for prostate cancer detection, is a unique prostate differentiation restricted chymotrypsin-like serine protease whose enzymatic activity, once secreted by normal or malignant prostate epithelial cells into the serum, is inhibited by serum inhibitors. Based upon these results, a collaboration was established between the Lilja laboratory at Lund and the Isaacs laboratory at Hopkins, with Sam Denmeade leading the Hopkins effort to identify specific peptide substrates whose efficient hydrolysis is restricted to PSA. This led to the identification of His-Ser-Ser-Lys-Leu-Gln-x-Leu (i.e., a 7AA peptide where -x- is the PSA cleavage site) as the lead peptide for such PSA-activated prodrug development. As an in vitro proof of principle for such a PSA-activated prodrug approach, we collaborated with Andrew V. Schally, Department of Medicine, Tulane University School of Medicine and Veterans Affairs Medical Center, New Orleans, Louisiana to couple the primary amine of doxorubicin via a peptide bond to the carboxylic acid group of the 7AA lead peptide. These studies documented that such a doxorubicin-peptide prodrug selectively kills cells that express enzymatically active PSA.

This approach was initially based upon the discovery by Hans Lilja at the University of Lund, Sweden, that Prostate-Specific Antigen (PSA), besides being a serum marker for prostate cancer detection, is a unique prostate differentiation restricted chymotrypsin-like serine protease whose enzymatic activity, once secreted by normal or malignant prostate epithelial cells into the serum, is inhibited by serum inhibitors. Based upon these results, a collaboration was established between the Lilja laboratory at Lund and the Isaacs laboratory at Hopkins, with Sam Denmeade leading the Hopkins effort to identify specific peptide substrates whose efficient hydrolysis is restricted to PSA. This led to the identification of His-Ser-Ser-Lys-Leu-Gln-x-Leu (i.e., a 7AA peptide where -x- is the PSA cleavage site) as the lead peptide for such PSA-activated prodrug development. As an in vitro proof of principle for such a PSA-activated prodrug approach, we collaborated with Andrew V. Schally, Department of Medicine, Tulane University School of Medicine and Veterans Affairs Medical Center, New Orleans, Louisiana to couple the primary amine of doxorubicin via a peptide bond to the carboxylic acid group of the 7AA lead peptide. These studies documented that such a doxorubicin-peptide prodrug selectively kills cells that express enzymatically active PSA.